It is now well established that genetic factors contribute to glaucoma, and several glaucoma-associated genes have been identified. The first identified and the most studied gene is MYOCILIN, which is highly expressed in the trabecular meshwork, one of the key components in the aqueous humor outflow system of the eye. Although MYOCILIN is expressed in both ocular and non-ocular tissues, the function of the encoded protein, myocilin, is still not fully understood. To develop a genetic mouse model induced by the synergistic interaction of mutated myocilin and another significant risk factor, oxidative stress, we produced double-mutant mice (Tg-MYOC-Y437H/+/Sod2+/-) bearing human MYOC with a Y437H point mutation and a heterozygous deletion of the gene for the primary antioxidant enzyme, superoxide dismutase 2 (SOD2). Accumulation of Y437H mutated myocilin in the trabecular meshwork induced serious endoplasmic reticulum stress and led to a 45% loss of smooth muscle alpha-actin positive trabecular meshwork cells in the eye drainage structures of 10-12 month-old Tg-MYOC-Y437H/+/Sod2+/- mice as compared with wild-type littermates. Tg-MYOC-Y437H/+/Sod2+/- mice had higher intraocular pressure, lost about 37% of retinal ganglion cells in the peripheral retina, and exhibited axonal degeneration in the retina and optic nerve as compared with their wild-type littermates. Single-mutant littermates containing MYOC-Y437H/+ or Sod2+/- exhibited no significant pathological changes until 12 months of age. Additionally, we observed expression of endothelial leukocyte adhesion molecule-1, a human glaucoma marker, in the TM of Tg-MYOC-Y437H/+/Sod2 +/- mice. Our data suggest that combined effects of mutated myocilin and enhanced oxidative stress lead to pathological changes similar to ones observed in human glaucoma patients. This is the first reported animal glaucoma model that combines expression of a glaucoma-causing mutation and a mutation mimicking a deleterious environment factor that act synergistically. We continued our investigations on the role of myocilin in the central (optic nerve) nervous system. We demonstrated that myocilin is a mediator of oligodendrocyte differentiation and is involved in the myelination of the optic nerve in mice. Myocilin is expressed and secreted by optic nerve astrocytes. Differentiation of optic nerve oligodendrocytes is delayed in Myocilin-null mice. Optic nerves of Myocilin-null mice contain reduced levels of several myelin-associated proteins including myelin basic protein, myelin proteolipid protein, and CNPase compared with those of wild-type littermates. This leads to reduced myelin sheath thickness of optic nerve axons in Myocilin-null mice compared with wild-type littermates, and this difference is more pronounced at early postnatal stages compared with adult mice. Myocilin also affects differentiation of oligodendrocyte precursors in vitro. Its addition to primary cultures of differentiating oligodendrocyte precursors increases levels of tested markers of oligodendrocyte differentiation and stimulates elongation of oligodendrocyte processes. Myocilin stimulation of oligodendrocyte differentiation occurs through the NgR1/Lingo-1 receptor complex. Myocilin physically interacts with Lingo-1 and may be considered as a Lingo-1 ligand. Myocilin-induced elongation of oligodendrocyte processes may be mediated by activation of FYN and suppression of RhoA GTPase. Interaction of myocilin with the NgR1/Lingo-1 complex opens a possibility that myocilin may be involved in the regulation of axon growth and regeneration. In collaboration with Dr. Vittorio Porciatti (Bascom Palmer Eye Institute, University of Miami Miller School of Medicine, Miami, Florida) we showed that transgenic mice expressing mutated human myocilin display progressive age-related changes in RGC electrical responsiveness that are not associated with IOP elevation but are associated with marked astrogliosis and axonopathy. Our results support the view that MYOCILIN expression in the optic nerve may impact structural, metabolic, or neurotrophic support to RGC axons, thereby influencing their susceptibility to glaucomatous damage independently of IOP.